The formation of cataracts is an intractable eye condition where an opacification of the lens is caused and which results in a loss of visual acuity. Various studies on a causal factor and mechanism of cataracts, and a treatment method therefor have been made. But at present, there are very few medical substances which are effective for cataracts.
It is reported that an increase of peroxide in the lens is related to a cause of cataracts and a chemical substance having suppressive effect on lipid peroxide formation is effective on treatment of cataracts (Current Eye Res., 5, 37 (1986)). It is also reported that protein denaturation is observed in lenses of cataract patients (Ophthalmology, 19, 1283 (1977)).
From the reports, a chemical substance which has suppressive effect on lipid peroxide formation in combination with protein stabilizing effect can be presumed to be especially useful for treatment of cataracts. A compound having the above both effects, however, has not been studied and the development of such a compound has been desired.
As the result of our precise study to find a compound having a suppressive effect on lipid peroxide formation in combination with a protein stabilizing effect, the inventors found that 1,4-thiazine or thiomorpholine derivatives, wherein the 2nd-position was substituted by a benzylidene group which was further substituted by hydroxy and lower alkyl groups and the 4th-position was substituted by an acidic group such as carboxy, tetrazolyl, phosphono or sulfonyl, exhibited both effects.
Some of 1,4-thiazine or thiomorpholine derivatives having a benzylidene substituent at the 2nd-position, where the chemical structure is common to the basic structure of the compounds of this invention, were reported to show an anti-allergic effect or tyrosinekinase inhibitory effect (Japanese Unexamined Patent Publication No. 29570/1987) or an ultraviolet light absorption effect (Japanese Unexamined Patent Publication No. 126676/1975 and 126677/1975). The description in the publications, however, is limited to 1,4-thiazine or thiomorpholine derivatives wherein the nitrogen atom, that is the 4-th position of the 1,4-thiazine or thiomorpholine ring, has no substituent or has a substituent of alkyl or aralkyl. Further the prior art discloses neither a protein stabilizing effect nor a suppressive effect on lipid peroxide formation.
Some of 2-benzylidene-3-oxo-1,4-benzothiazine derivatives having a ring system formed by a condensation of a thiazine ring and a phenyl ring were reported to show an active oxygen elimination effect or a suppressive effect on lipid peroxide formation (Japanese Unexamined Patent Publication No. 287077/1989).
In the meantime, recently the utility of aldose reductase inhibitors for treatment of cataract has attracted attention. The compound of this invention also has an aldose reductase inhibiting effect and is very useful for the treatment of cataracts.